N-acyl sydnonimine derivatives

ABSTRACT

DERIVATIVES OF THE SYDONIMINES ACCORDING TO U.S. PAT. NO. 3,312,690, WHEREIN THE IMINO GROUP IS REPLACED BY N-FORMYL, N-ACETYL, N-PROPIONYL, N-MONOCHLORO ACETYL, N-DICHLORO ACETYL, N-TRICHLORO ACETYL, N-TRIFLUORO ACETYL, N-PHENOXY ACETYL, N-PHENOXY PROPIONYL, N-PHENYL ACETYL, N-PHENYL PROPIONYL, N-CINNAMOYL, N-BENZOYL, N-ETHOXY CARBONYL, N-BENZYLOXY CARBONYL, N-METHYL, CARBAMOYL, N-ETHYL CARBAMOYL, N-PHENYL CARBAMOYL, N-NICOTINOYL, N-ISONICOTINOYL, N-(N&#39;&#39;-CARBOBENZYLOXY ALAYL), NMETHYL SULFONYL, N-PHENYL SULFONYL, N-P-CHLOROPHENYL SULFONYL, N-NITROSO, ETC., AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF HAVE SUPERIOR UTILITY AS HYPOTENSIVE DRUGS, CORONARY AND PERIPHERAL VESSEL DILATORS OR MUSCLE RELAXANTS. THE 3-POSITIONED   R1-N(-R2)-GROUP   MAY ALSO BE AN   (ARALKYL)2-N-GROUP   EACH ARALKYL HAVING 7 TO 9 CARBON ATOMS.

United States Patent U.s .-cl. 260247.2 A Claims ABSTRACT OF 'THEDISCLOSURE Ngroup may also be an aralkyl group aralky each aralkylhaving 7 to 9' carbon atoms.

I This application is a continuation-in-part of application Ser. No,651,137, filed July 5, 1967, and now abandoned.

This invention relates to novel medicinally useful sydnonimines of thetype of the sydnonimines of US. Pat-No. 3,312,690:

(the variables being as defined in the patent), wherein the hydrogenatom of the =NH group of the latter is replaced "by a nitroso group orby an acyl group,- and wherein 'R{ and R may also be aralkyl, ashereinafter defined. The invention also encompasses the pharmaceuticallyacceptable acid addition salts of the new compounds. The said 'newcompounds correspond to the formula wherein R is hydrogen or alkylhaving 1 to S carbon atoms, each of R and R is alkyl having 1 to 5carbon atoms or phenyl alkyl having 7 to 9' carbon atoms, or

ice

R and R taken together with" the adjacent N-atom representmorpholino,pipecolino,

(CHl)nN J wherein n is 4, 5 or 6,

zv-fiwherein R is alkyl having 1 to 5 carbon atoms or wherein R is asprecedingly defined, R in each case represents -NO, R CO-- wherein R isalkyl, halo alkyl, phenoxyalkyl, phenyl alkyl, phenyl alkenyl,alkanoylalkyl, alkoxy or phenyl alkoxy, said groups having up to ninecarbon atoms respectively, or hydrogen, phenyl, phenyl amino, pyridyl orl-(carbobenzyloxy amino) ethyl, or R SO wherein R is halo phenyl oracetylaminophenyl.

Compounds I and their pharmaceutically acceptable acid addition saltshave characteristic effects as hypotensive drugs, coronary andperipheral vessel dilators or muscle relaxants. The new compounds andtheir salts of this invention are also characterized by the rapiditywith which, after administration, they manifest their bloodpressurelowering effect, and also by the extended time of persistence of sucheffect; moreover, the said new compounds and their salts show arelatively low acute toxicity. In addition, the said compounds I andtheir salts are effective in relaxing muscles and relaxing coronaryvessels. Thus, they are useful as medicines for the therapy ofhypertension, Raynauds disease, etc.

In Formula I, R stands for H or alkyl having one to five carbon atomssuch as methyl, ethyl, propyl, n-butyl, isobutyl, amyl, R stands for (1)the ON-group, or (2) an R CO-- wherein R is alkyl having up to ninecarbon atoms such as methyl, ethyl, propyl, n-butyl, tert-butyl andamyl, halo alkyl having up to nine carbon atoms such asmonochloromethyl, dichloromethyl, trichloromethyl, monofiuoromethyl,difluoro methyl, trifluoromethyl, monochloroethyl, dichloroethyl andtrifluoroethyl, phenoxyalkyl having up to nine carbon atoms such asphenoxymethyl and phenoxyethyl, phenyl alkyl having up to nine carbonatoms such as benzyl and phenylethyl, phenyl alkenyl having up to ninecarbon atoms such as styryl, alkanoyl alkyl having up to nine carbonatoms such as acetyl methyl and propionyl ethyl, alkoxy having up tonine carbon atoms such as methoxy, ethoxy, propoxy, n-butoxy,tert-butoxy and t-amyloxy, phenyl alkoxy having up to nine carbon atomssuch as benzyloxy, hydrogen, phenyl, phenylamino,l-(carbobenzyloxyamino) ethyl, pyridyl group such as 2-pyridyl,3-pyridyl and 4-pyridyl, or (3) R SO wherein R is halo phenyl such I aso-chlorophenyl, m-chlorophenyl, p-chlorophenyl, or

p-acetyl aminophenyl, and R and R each stands for alkyl having one tofive carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl,tert-butyl, amyl, or phenyl alkyl having seven to nine carbon atoms,such as benzyl, phenyl ethyl, phenyl propyl, and R and R may formtogether with the adjacent nitrogen atom-a ring such as morpholino,pipecolino,

wherein in is 4, 5 or 6, which is examplified by piperidino,pyrrolidino, or hexahydroazepinyl,

Ii -4m- 3 wherein R is alkyl having as methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl or amyl, or

3-morpholino-N-formyl sydnonimine; 3-morpholino-N-acetyl sydnonimine;3-morpholino-N-propionyl sydnonimine; 3-morpholino-N-monochloro acetylsydnonimine; 3-morpholino-N-dichlono acetyl sydnonimine;S-morpholino-N-trichloro acetyl sydnonimine; 3-morpholino-N-trifluoroacetyl sydnonimine; 3-morpholino-N-phenoxy acetyl sydnonimine;3-morpholino-N-phenoxy propionyl sydnonimine; 3-morpholino-N-phenylacetyl sydnonimine; 3-morpholino-N-phenyl propionyl sydnonimine;3-morpholino-N-cinnamoyl sydnonimine; 3-morpholino-N-benzoylsydnonimine; 3-morpholino-N-methoxy carbonyl sydnonimine;3-morpholino-N-ethoxy carbonyl sydnonimine; 3-morpholino-N-propoxycarbonyl sydnonimine; 3-morpholino-N-benzyloxy carbonyl sydnonimine;3-morpholino-N-methyl carbamoyl sydnonimine; 3-morpholino-N-ethy1carbamoyl sydnonimine; 3-morpholino-N-phenyl carbamoyl sydnonimine;3-morpholino-N-nicotinoy1 sydnonimine; 3-morpholino-N-isonicotinoylsydnonimine; 3-morpholino-4-methyl-N-benzoyl sydnonimine;3-morpholino-4-ethyl-N-benzoyl sydnonimine; 3-dimethylamino-N-benzoylsydnonimine; 3-dimethylamino-4-methyl-N benzoyl sydnonimine;3-morpholino-N-(N'-carbobenzyloxy alanyl) sydnonimine;3-morpholino-N-methyl sulfonyl sydnonimine; 3-morpholino-N-phenylsulfonyl sydnonimine; 3-morpholino-N-n-chlorophenyl sulfonylsydnonimine; 3-morpholino-N-nitroso sydnonimine;3-diethylamino-N-benzoyl sydnonimine; 3-di-n-butyl amino N-nitrososydnonimine; 3-di-n-butylamino-N-ben2oyl sydnonimine; 3-dibenzylamino-4-methy1-N-nitroso sydnonimine; 3-piperidino-N-benzoylsydnonimine; 3-piperidino-N-nitroso sydnonimine;3-hexahydroazepinyl-N-nitroso sydnonimine; 3-a-pipecolino-N-benzoylsydnonimine; 3-pyrrolidino-N-nitroso sydnonimine; 3-(N-methylpiperazino)-N-nitroso sydnonimine;3,3'-(1,4-piperazino-diyl)-N,N-dinitroso bis sydnonimine; 3-a-pipecolino-N-nitroso sydnonimine,'etc.

Compounds I of the present invention are produced by acylating acorresponding compound of the Formula II one to live carbon atoms suchwherein R R and R have respectively the same mean said -Pat;-No;3,312,690, the method being shown by the following equation:

wherein R R and R have respectively the same meanings as above. Thereaction of the present invention is carried out by reacting a startingmaterial of the above Formula II with an acylating agent for introducingthe desired group (ON, R CO or R SO onto the nitrogen atom bound to the5-positioned carbon atom of the starting materials.

The introduction of the -NO group iseifected in conventional manner perse known, for example, by reacting a starting material of the Formula IIwith a nitroso compound, such as alkali metal nitrite (e.g., sodiumnitrite, potassium nitrite) or ammonium nitrite in an aqueous mediumpreferably under cooling, or by passing nitrous acid fumes into asolution or suspension of the starting material preferably undercooling, in an organic solvent such as pyridine or an inorganic solventsuch as water or a mixture thereof. i. Y 1

The introduction of an R CO or R SO group is effected in per se knownmanner, for example, by reacting the starting material of- Formula IIwith a reactive derivative of the corresponding acid R COOH or R SO H,such as an acid halide (e.g., acid. chloride,'acid bromide, acid iodide,acid fluoride), an acid anhydride, acid ester, ketene or isocyanate,preferably under cooling, in water or an organic solvent such asalcohol, pyridine, acetonitrile, ether, with the use of an acideliminating agent such as an alkaline substance (e.g., sodium hydroxide,sodium bicarbonate, sodium'carbonate) or an amine compound (e.g.,triethyl amine, pyridine);

Thus, the desired N-acyl sydnonimine derivatives I are produced as freebase or acid salts. When the objective compounds are obtained as freebase, these compounds may be converted into their pharmaceuticallyacceptable salts of a mineral acid (e.g., hydrochloric, nitric,sulfuric, phosphoric acid, etc.), or of an organic acid (e.g., formic,acetic, butyric, citric, ascorbic, salicylic, p-aminosalicylic acid,etc.).

The present N-acyl sydnonimine derivatives (I) or their salts areadvantageously administered'in the form of an aqueous solutioncontaining about 1 milligram of N- acyl'sydn'onimine per milliliter ofwater and are generally administered per os but injection can also beapplied, the dose for an adult being within the range from 'aboutS toabout milligrams per day.

For the purpose of giving those skilled in the art a betterunderstanding of the invention, the following illustrative tests andexamples are given.

TEST FOR DEPRESSOR RESPONSE The compounds of the present invention wererespectively administered to a stomach or a duodenum of an anestehtizedcat with pyloricligated stomach through a tube previously put into thestomach or the duodenum. At various intervals after-the administration,the systolic and diastolicblood pressure of the cat was measured with ahaemodynamometer to determine the percent change ,769 2 5.. 6 of droppedpressure. The results of the tests are as folhydrochloride suspended ina mixture of 200 parts by v o1- low ume of acetic anhydride and 40 partsby volume of 'pyri-l Percent change of dropped pre ure,,s tJdlast. v v

Compound tration mg./kg. min. min. min. min. min,

3-morpholino-N-benzoyl sydnonimine hydrochloride.;.:....{g I v i 8 g 3,;g 8

Control (B-morphollno-sydnonlnnne) hydrochloride 1 N.B.; G=Intra-gastrleadministration: D=Intra-duodenum administration.

From the results of the test, it can be seen that the dine are agitatedfor 48 hours at room temperature (about hitherto-known sydnonimine testcompound is absorbed 15 15 to about 30 0.), whereby precipitates areformed.

only from the duodenum and is scarcely absorbed from The precipitatesare collected by filtration and are rethe stomach. In sharp contrast,the test compounds (I) crystallized from about 700 parts by volume ofethanol of this invention are absorbed not only from the duodeto give20.3 parts by weight (84%) of 3-morpholino-N- nurn but also from thestomach in large amount. This demacetyl sydnonimine hydrochloride havinga melting point onstrates that the compounds (I) of this invention showof 175 C. (with decomposition). their activities more rapidly than thecontrol compound. Analysis.-Calculated for C H N O Cl (percent): C,

TEST FOR HYPOTENSIVE EFFECT H,2 N, 22.53. Found (percent): C, 38.77; H,

The compounds of the present invention were severally EXAMPLE 2administered orally to Nembutal-anesthetized dogs (5 To 10 parts byweight of 3 morpholinosydnonimine kg.) and the blood pressure of therespective test dog was hydrochloride Suspended in 25 parts by weight fPyri f f f measured by a haemodynamometer 3 the dine, there are addeddropwise under ice-cooling and with distinctions of the blood pressurebefore the admmrstrastirring i0 parts by Weight of benzoyl chloride, andthen tion and at various intervals after the administration were themixture is agitated for 4 hours crude crystals being determined thedisfinctions being indicated as dropped formed. The crude crystals thusobtained are collected by blood Pressure Table II: filtration, washedwith 75 parts by volume of water, and

recrystallized from 500 parts by volume of absolute meth- TABLE II anolto yield 5.5 parts by weight of 3-morpholino-N-ben- Dropped bloodpressure mnL/Hg zoylsydnonimine having a melting point of 186 to 188 C.

m 20 3o 60 120 180 5.5 parts by weight of thus-obtained 3-morpholino-N-Compound mm mm mm m, benzoyl sydnonimine is dissolved in methanolichydrochloric acid, and the solvent is evaporated off under re- -30 4,2duced pressure, crude crystals being formed. Recrystalliza- 40 tion ofthe crude crystals from methanol gives 6.0 parts N0'rE.Compound(1):3-morpholino-N-ethoxycerbonyl sydnonimine; by Weight 0f3-morpholino-N-benzoyl syndonimine hy- Compound (2):3-ruorpho1ino-N-benzoyl sydnonimine hydrochloride; d hl id h i a l ipoint f 159 to 160 i h Control com ound 3 :B-mor holino s dnonimine hdrochloride.

p p y y decomposition) Analysis.-Calculated for C H N O Cl (percent): C,The (12 and (2) the 45 50.25; H, 4.87; N, 18.03. Found (percent): 0,50.35; H, are more effective, and have a longer eifective duratlon Nthan the control compound (3) in lowering blood-pressure. In a mannerSimilar to the above, the following TEST FOR ACUTE TOXICITY pounds areobtained: The compounds of this invention were administered 3diithylamino N benzoyl sydnonimine, intraperitioneally to groups, eachconsisting of four mice (male, 4 weeks old, ICRJCL strain)3-p1per1dmo-N-benzoyl sydnonimine, M.P. 175 C.

Thus-administered mice were observed for 30 days to 'jP P Y y l 116118C. count the number of mice killed within the period and3'dl'n'butylamlno'N'benloyl sydnommme' to measure the time of decease ofthe last-killed mouse (colorless oily substance) LR. absorption cmr1610, within the said period. The results are as follows: 1580, 1550.

TABLE 3 Number of killed mouse or mice Dose, mgJkgJ. 1,000 500 250 125Compound:

3-morphollno-N-benzoyl sydnonimine hydrochloride 4, mmutes..-- 0 0 0B-morpholino-Nethoxy carbonyl sydnonimine. 0 n n 03-morpholino-N-p-chlorobenzenesulfonyl sydnonimine- 0 n n 03-morpholino-N-nittoso sydnonimine 1, 12 hours 0 0 03-morpholino-N-aeetyl sydnonimine hydrochloride.-- 4, 15 utes 0 0 0Control 3-morpholino sydnonmine/hydrochloride 4, 10 mlnutes.. 4, 15minutes. 1, 40 mlnutes 0 1 Milligrams per kilograms. The compounds (I)of this invntion are thus shown to EXAMPLE 3 have remarkably lesstoxicity in comparison with the con- To 1.0 part by weight of3-morpholinosydnonimine hytrol compound. drochloride suspended in 5parts by volume of pyridine, The following examples are illustrative ofpresently there are added dropwise, under ice-cooling and with preferredexemplary embodiments of this invention. In st rring, 1.2 parts byWeight of p-chlorophenyl sulfonyl these examples, parts by weight bearthe same relationship chlorlde, and the mixture is agitated overnight atroom to parts b ol as do grams t illilit temperature, whereby crystalsare formed, followed by EXAMPLE 1 add tion of 30 parts by volume ofwater. The mixture is sub ected to filtration to obtain 1.5 parts byweight of Twenty parts by weight of 3-morpholinosydnonimine crudecrystals which are recrystallized from about 200 parts by volume ofethanol to, give 1.3 partsby weight (78%) of3-morpholino-N-p-chlorophenyl sulfonyl syd'- nonimine melting at 178 to,179 C. (with decomposition) 7 1.6 parts by volume of ethyl chloroformateis stirred dropwise into a suspension of 1.0 part by weight of 3-morpholinosydnonimine hydrochloride in parts by volume of pyridine, andthe mixture is agitated for a while to allow reaction to take place.Pyridine is removed from the reaction mixture by evaporation, and theresidue is dissolved in a small amount of water and extracted withchloroform several times. The extractant is dehydrated by addinganhydrous magnesium sulfate and subjected to filtration. Chloroform isremoved from the filtrate by distillation, crude crystals beingobtained. Recrystallization of the crude crystals from toluene gives 0.6part by weight of 3-morpholino-N-carboethoxysydnonimine having a meltingpoint of 140 to 141 C. Yield 51%.

Analysis.-Calculated for C H N O (percent): C, 44.62; H, 5.83; N, 23.13.Found (percent): C, 44.57; H, 5.85; N, 23.19.

EXAMPLE 5 To 2.0 parts by weight of 3-morpholinosydnoniminehydrochloride dissolved in 20 parts by volume of water, there are added,under ice-cooling and with stirring, 0.9 part by weight of sodiumbicarbonate and, after 5 minutes, there is further added 1.2 parts byweight of phenyl isocyanate. The mixture is then agitated for 6 hoursand kept standing overnight, the resultant precipitates being separatedfrom the reaction mixture by filtration. Thusrecovered precipitates aresubjected to column chromatography to remove contaminant diphenylurea.Recrystallization of thus-treated crude crystals from methanol gives 0.8part by weight of 3-morpholino-N-phenyl carbamoyl syndnonimine having amelting point of 162 C. (with decomposition).

AnaZysis.Calculated for C H N O (percent): C, 53.97; H, 5.23; N, 24.21.Found (percent): C, 54.04; H, 5.53; N, 24.29.

By the same procedure as above, the precipitates are separated from thereaction mixture by filtration, and are then dissolved in methanolichydrochloric acid, after which the methanol is distilled ofi. from thesolution. The residue is washed with acetone to remove diphenylurea,crude 3- morpholino-N-pheny1 carbamoyl syndnonimine hydrochloride beingobtained. Recrystallization of the crude compound from methanol givescrystals having a melting point of 175 to 176 C. (with decomposition).

Analysis.-Calculated for C H N O Cl (percent): C, 47.93; H, 4.95; N,21.50. Found (percent): C, 47.86; H, 4.96; N, 21.57.

EXAMPLE 6 36.18; H, 4.55; N, 35.16. Found (percent): C, 36.06; H,

8 EXAMPLE 7 7 Two partsby weight of 3- morpholinosydnonimine hy:drochloride are dissolved in an excess of trifiuoro-acet'ic acidanhydride. After standing overnight, the mixture is concentrated todryness under highly reduced pressure. Thus-yielded crude crystals arecarefully recrystallized from ethanol to obtain 2.3 parts by weight(89.5%) of pure 3-morpholino-N-trifluoroacetyl sydnonimine having amelting point of 167 to 168 C. (with decomposition).

AnaIysis.-Calculated for C H N OF (percent): C, 36.10; H, 3.41; N,21.05. Found (percent): C, 36.22; H, 3.72; N, 21.69.

EXAMPLE 8 To 3.0 parts by weight of 3-morpholinosydnoniminehydrochloride suspended in 30 parts by volume of water, there are added1.3 parts by weight of sodium bicarbonate under ice-cooling and withstirring, after which the mixture is further agitated for about 10minutes. To the thus treated mixture, there is added dropwise underice-cooling, 3.0 parts by weight of p-nitrophenyl formate dissolved in20 parts by volume of tetrahydrofuran. The mixture solution is furtheragitated two hours, the temperature of the reaction system rising toroom temperature. After the tetrahydrofuran is distilled oil from thereaction mixture, p-nitrophenol and unreacted reagent are removed byextraction with ether, and then, from the thus-treated reaction mixture,the objective compound is extracted several times with ethyl acetate.

After being dried, the extractant is subjected to distillation to removethe solvent to leave crude crystals of 3-morpholino-N-formylsydnonimine. The crude crystals are recrystallizedfrom ethanol to obtain 2.3 parts by weight of pure crystals having amelting point of 149 to 151 C. (with decomposition).

Analysis.-Calculated for C H N O' "(percent):' C, 42.42; H, 5.09; N,28.27. Found (percent): C, 42.25; H, 5.17; N, 28.47.

The objective compound can also be produced by the following process:3.0 parts by weight of 3-morpholinosydnonimine hydrochloride aredissolved in an excess amount of formic acid anhydride. After standingovernight, the mixture is concentrated to dryness. Thus-obtained crudecrystals are recrystallized from ethanol to yield 2.5 parts by weight(87%) of 3-morpholino-N- formyl sydnonimine.

EXAMPLE 9 To 4.0 parts by weight of 3-morpholinosydnoniminehydrochloride suspended in 40 parts by volume of water, there are added1.7 parts by weight of sodium bicarbonate under ice-cooling andagitation, and the mixture is further agitated for about 10 minutes. Tothe thus-treated mixture there is added dropwise, under'ice-coolingandwith stirring, 4.5 parts by weight of p-nitrophenyl monochloroacetatedissolved in 20 parts by volume of tetrahydrofuran. Thus-resultingmixture is stirred for further 2 hours, the temperature of the reactionsystem risingto room temperature. Tetrahydrofuran is distilled 01f fromthe reaction mixture, and to the residue there is added water, crudecrystals being preicpitated. The crystals are washed with water andether and are then recrystallized from ether to obtain 4.5 parts byweight (91%) of 3-morpholino-N- monochloroacetyl sydnonimine having amelting point of to 107 C. I

Analysis.Calculated for C H N O Cl (percent): C, 38.95; H, 4.50;N,22.72. Found (percent): C, 39.07; H, 4.56; N, 22.61.

7 EXAMPLE 10 In a similar manner to Example 9, 4.0 parts by weight of3-morpholinosydnonimine hydrochloride is reacted with 5 9: parts byweight of p-nitrophenyl dichloroacetate to obtain 5.0 parts, by weightv(789% of 3 -rnorphqlino N-di chloroacetyl sydnonimine having a meltingpoint of 165 to 167 C.' (with decomposition). 7

34.18;;H, 3.59; N, 19.93. Found (percent): C, 3.52; N, 19.91.

' EXAMPLE 11 Into 3.1 parts by weight of 3-morpholinosydnoniminehydrochloride suspended in 25 parts by volume of dry pyridine, there arestirred 3 parts by weight of trichloroacetyl chloride under ice-cooling,and the mixture is then further agitated for 4 hours at a temperature of5 to C.

The reaction mixture is cooled again with ice, and about 50 parts byvolume of water is then added to the thustreated mixture, crude crystalsbeing precipitated. After recovering the crystals by filtration, theyare washed with water, and then recrystallized from ethanol to yield 4.5parts by weight (95%) of crystals of 3-morpholino-N- trichloroacetylsydnonimine having a melting point of 180 to 181.5" C. (withdecomposition).

Analysis.Calculated for C H N O Cl (percent): C, 30.45; H, 2.87; N,17.76. Found (percent): C, 30.25; H, 2.74; N, 17.90.

EXAMPLE 12 3.0 parts by weight of 3-morpholinosydnonimine hydrochlorideare suspended in a mixture of 19.0 parts by weight of propionic acidanhydride and 4 parts by volume of pyridine, followed by stirring forabout 20 hours at room temperature, white crystals being precipitated.The crystals, collected by filtration, are recrystallized fromisopropanol to obtain 3.2 parts by weight of 3-morpholino- N-propionylsydnonimine hydrochloride having a melting point of 169 to 171 C. (withdecomposition).

Analysis-Calculated for C H N O Cl (percent): C, 41.45; H, 5.76; N,21.33. Found (percent): C, 41.42; H, 5.78; N, 21.23.

EXAMPLE 13 Into 2.0 parts by weight of 3-morpholinosydnoniminchydrochloride suspended in 15 parts by volume of pyridine, there arestirred dropwise 1.7 parts by weight of phenyl propionyl chloride underice-cooling. After allowing the reaction mixture to stand overnight,pyridine is distilled off therefrom under reduced pressure, and theresulting oily substance is washed with ether to remove impurities.

Thereupon, the oily substance is subjected to silica gel columnchromatography, using ethyl acetate as solvent. Concentration of the"eluate gives 0.5 parts by weight of powdery product. This powderyproduct is recrystallized from methanol to obtain 0.3 part by weight ofneedle crystals of 3-morpholino-N-phenyl propionyl sydnonimine havingamelting point of 127 to 129 C.

Analysis- Calculated for C H N O (percent): C, 59.59;H, 5.96; N, 18.53.Found (percent): C, 59.46; H, 6.02; N, 18.15.

EXAMPLE 14 Into 2.0 parts by weight of 3-morpholinosydnoniminehydrochloride suspended in 15 parts by volume of pyridine, there arestirred under ice-cooling 2.5 parts by weight of cinnamoyl chloride.After the mixture is allowed to stand overnight, water is added thereto,pyridine hydrochloride dissolves in the water and crystals separate out.After recovering the crystals by filtration, they are recrystallizedfrom ethanol to obtain 2 parts by weight of flake crystals of3-rnorpholino-N-cinnamoylsydnonimine having a melting point of 184 to187 C.

Analysis.-Calculated for C H N O (percent): C, 59.99; H, 5.37; N, 18.66.Found (percent): C, 59.85; H, 5.46; N, 18.54.

EXAMPLE 15 Into 1.0 part' by" weight of 3 -dimethylaminosydnoniminehydrochloride/suspendedin 5"parts by volume of pyridine, thereis'stirred 1.2 parts .by 'Weight of benzoyl chloride, under ice-cooling,after which the mixture is agitated further 2 hours.

After the mixture has. been allowed to stand overnight, there is furtheradded thereto 1.0 part by weight of benzoyl chloride, followed bystirring.

Thus-prepared mixture is subjected to distillation under reducedpressure at a temperature below 40 C. to remove the solvent. Theresulting residue is dissolved in chloroform, and the chloroform layeris washed with water, dehydrated by magnesium sulfate and subjected todistillation to remove chloroform, whereby brown oily substance isproduced. The oily substance is then purified by means of silica gelchromatography (solvent: ethyl acetate) to obtain crude crystals.Recrystallization of the crude crystals from ethanol gives 0.8 part byweight of 3-dimethylamino-N-benzoyl sydnonimine having a melting pointof 127 to 128 C.

Analysis.-Calculated for C H N O (percent): C, 56.89; H, 5.21; N, 24.13.Found (percent): C, 56.81; H, 5.20; N, 24.31.

EXAMPLE 16 Into 1.0 part by weight of3-dimethylamino-4-methylsydnonimine hydrochloride suspended in 3 partsby volume of pyridine, there is stirred 1 part by weight of benzoylchloride under ice-cooling, followed b further stirring for 4 hours. Themixture is subjected to distillation to remove pyridine, and theresulting residue is dissolved in ethyl acetate and decolored byactivated charcoal.

Thus-treated solution is concentrated to precipitate crude crystals.Recrystallization of the crude crystals from methanol yields 0.1 part byWeight of 3-dimethylamino- 4-methyl-N-benzoyl sydnonimine having amelting point of 109 C. to 110 C.

Analysis.Calculated for C H N O (percent): C, 58.52; H, 5.73; N, 22.75.Found (percent): C, 58.60; H, 5.85; N, 22.74.

EXAMPLE 17 Into 1.0 .part by weight of 3-morpholinosydnoniminehydrochloride suspended in 5 parts by volume of dry pyridine, there isstirred dropwise 1.0 part by weight of phenoxy acetyl chloride underice-cooling, followed by continued agitation for 10 hours. 0.6 part byweight of phenoxy acetyl chloride is further added to the mixture,followed by stirring for 8 hours. To the resultant mixture, there isadded 50 parts by volume of water, and the aqueous layer is separatedfrom the oily layer by decantation. Crystals separated from the aqueouslayer are collected by filtration and recrystallized from ethanol toobtain 0.15 part by weight of 3-morpholino-N-phenoxy acetyl sydnonimine.

On the other hand, the oily layer is dissolved in ethyl acetate, anddried with magnesium sulfate. The solvent is distilled 01? from thesolution to yield brown oily residue. The residue is purified by meansof silica gel column chromatography (solvent: ethyl acetate) to obtain0.2 part by weight of crystals.

Recrystallization of the crystals from ethanol gives 05 EXAMPLE 1s Into1.0 part by weight of 3-morpholinosydnonimine hydrochloride dissolved ina small amount of water, there. is stirred 0.8 part by weight of sodiumbicarbonate, and then 0.8 part by weight of carbobenzoxy chlorideundervice-cooling. To the mixture, there is then added a small amount ofmethanol, followed by allowing the mixture to standfor a fCWf-hOUIS toprecipitate crystals.=

-The solvent is :distilledxoffx from the filtratemndenreduced pressureto separate additional crystals; a

Recrystallization'of the" combined crystals frommethanol gives 0.7 partby weight of 3-morpholino-N-carbobenzoxyl sydnonimine having a meltingpoint of 115 to 116 C. as flake crystals. .1.

Analysis.-Calculated for C H N O (percent): C, 55.26; H, 5.30; N,18.41.:Found (percent): C, 55.39; H, 5.29; N, 19.10. i 1

' EXAMPLE 19 To 1.0 part by weight of 3-morpholin0 sydnoniminehydrochloride dissolved in a small amount of water there is added 0.4part by weight of sodium bicarbonate, after which 0.4 part by weight ofdiketene is stirred in dropwise under ice-cooling.

After stirring further for about two hours, the mixture becomes cloudyand crystals are precipitated. The crystals are collected by filtrationand washed with water to obtain 1.0 part by weight of crude crystals.These crude crystals are recrystallized from methanol to yield 0.6 partby weight of 3-morpholino-N-acetoacetylsydnonimine having a meltingpoint of 110-113 C. as flake crystals.

Analysis.Calculated for C H N O (percent): C, 47.24; H, 5.55; N, 22.04.Found (percent): C, 47.30; H, 5.33; N, 21.25.

EXAMPLE 20 A mixture of 2.7 parts by weight of N-carbobenzyloxy-L-alanine, 2.5 parts by weight of dicyclohexylcarbodiimide and 100 partsby volume of acetonitrile is stirred for two hours at room temperature.To the thus-treated mixture, there are added 2.0 parts by weight of3-morpholino sydnonimine hydrochloride and 1.6 parts by weight of drypyridine, and the mixture is stirred for about ten hours.

Separated precipitates comprising dicyclohexylurea, unreacted3-morpholinosydnonimine hydrochloride, etc. are removed by filtrationand the filtrate is concentrated under reduced pressure to obtain anoily substance. The oily substance is subjected to silica gelchromatography (silica gel column: 6 x 10 cm.; solvent: ethyl acetate;volume of 1 fraction: ml.) and fraction numbers from 27 to 70, arecombined together, followed by concentration under reduced pressure.Thus-obtained residue is recrystallized from a mixture of ethyl acetateand ethyl ether to obtain 0.94 part by weight (24%) of 3-morpholino-N-(N'-carbobenzyloxy-L-alanyl) sydnonimine having a melting point of108110 C.

Analysis.-Calculated for C17H21N5O5 (percent): C, 54.39; H, 5.64; N,18.66. Found (percent): C, 54.13; H, 5.49; N, 18.70.

EXAMPLE 21 Into 2.0 parts by weight of 3-morpholinosydnoniminehydrochloride suspended in parts by volume of water, there is stirred0.9 part by weight of sodium bicarbonate under ice-cooling, after whichthe mixture is further stirred for about ten minutes. To the' mixture,there is then stirred 4' parts by weight of N-carbobenzyloxy-L-alanyl-p-nitrophenyl ester in 10 parts by volume of tetra hydrofuranunder ice-cooling, and then the mixture is further agitated for twohours, whereby the temperature of the reaction system rises to roomtemperature..'1.0-part by weight of sodium bicarbonate is added to thereaction mixture and the mixture is extracted with ethyl acetate threetimes. The extractant is dried and the solvent is removed byconcentration under reduced pressure. Thusseparated oilysubstanceispurified'by means of silica-gel column chromatography after the mannerof Example'20 to" obtain 2.1 parts by Weight (56%) 'of 3'morpholino-N-(N'-carbobenzyloxy-L-alanyl) sydnonimine having a melting point of108-110" C.

' 0.29 part by volume" of ethylchloroformateare stirred dropwise into amixture of 0.67 part by weight of N-carbobenzoxy-L-alanine, 0.42 part byvolume of triethylamine and- 6 partsby volume of tetrahydrofurau undericecooling, andthen themixture is further stirred for about 15 minutes.'Into the reaction mixture thereis then stirred dropwise underice-cooling a suspension which is prepared by reacting 0.6 part, byweight of 3-morpholinosydnonimine hydrochloride, with 0.26 part byweight of sodium bicarbonate in 6 parts by volume of water undericecooling and with stirring, followed by further stirring for 1 hour,the temperature of .the reaction system rising to room temperature. Thereaction mixture is then extracted three times with ethylacetate. Theextractant is dried, and the solvent is distilledoff under reducedpressure. Thusobtained residue is washed with ethyl ether, and thenrecrystallized from ethyl acetate-ethylether to give 0.86 part by weight(76%) of 3rmorpholino-N-(N-carbobenzoxy-L-alanyl) sydnonimine. r

EXAMPLE" '23 To 1.2 parts by weight of nicotinic acid suspended in 10parts by volume of dry tetrahydrofuran, there are added 1.1 parts byweight of'ethylchloroformate and 1.0 part by weight of triethylamineunder cooling, the precipitated crystals of triethylamine hydrochloridebeing removed by filtration to obtain 'a mixed anhydride solution as thefiltrate.

On the other hand, to 2.0 parts by Weight of 3-morpholino-sydnoniminehydrochloride dissolved in a small amount of water, there is added undercooling 0.8 part by weight of sodium. bicarbonate and then'the filtrateobtained above is added dropwise. The resultant solution is extractedwith ethylacetateA'fte'r the extractant is dried, the solvent is removedunder reduced pressure to give crude crystals. Recrystallization of "thecrude crystals from methanol gives 0.3 part by weight'of 3-morpholino-N-nicotinoylsydnonimine having a melting point of 202 to204C.

Analysis-Calculated for C H N O '(percent): C, 52.36; H, 4.76; N, 25.44.Foun (percent) C, 52108; H, 4.70; N, 25.80. i

EXAMPLE 24 After the manner of 'Example 6, the following compounds areobtained from the corresponding reactants:

-3 piperidino-N-nitroso sydnonimine, M.P. 124 (with decomposition) v3edibutylamino-N-nitroso sydnonimine, M.P. 53 3-dibenzylamino-4methyl-N-nitroso sydnonimine, M.P.

103-106? (with decomposition) I a I 3-pyrrolidino-N-nitroso sydnonimine,M.P. 132-134 (with decomposition) 3-ot-pipecolino-N-nitroso.sydnonimine, M.P. 253 554" (with decomposition) H 3,3'-(1,4piperazino-diyl)-N,N-dinitroso bis sydnonimine,

M.P.168-169 (with decomposition) 3 -(N-methylpiperazino)-N-nitrososydnonimine, M.P.

132-133 (with decomposition).

What is claimed is:

1. A compound according to claim 4, namely, 3-morpholino-N-benzoylsydnonimine.

2. A compound according to claim 4, namely, 3-m0rpholino-N-carboethoxysydnonimine.

3. A pharmaceutically acceptable salt of a compound according to claim4.

4. A compound of the formula wherein R is H or alkyl having one to fivecarbon atoms and R is 14 carbon atoms, acetylmethyl, propionylethyl,alkoxy having 1 to 5 carbon atoms, phenylalkoxy having 7 to 9 carbonatoms, hydrogen, phenyl, phenylamino, pyridyl or l-(carbobenzyloxyamino)-ethyl, or (c) R SO wherein R is monochlorophenyl orpacetylaminophenyl. 5. A compound according to claim 4, namely,3-morpholino-N-acetyl sydnonimine.

References Cited UNITED STATES PATENTS 3,277,108 10/1966 Daeniker260-307 3,312,690 4/1967 Masuda et a1. 260-239 ALEX MAZEL, PrimaryExaminer J. TOVAR, Assistant Examiner US. Cl. X.R.

20 260240 U, 247.1, 247.2 B, 268 N, 293.69, 295 K, 295.5

